PROJECT SUMMARY The activity patterns of millions of neurons organized in circuits distributed across multiple brain regions mediate our interaction with the outside world. Current technologies for neuronal activity mapping such as electrodes, or optical modalities such as microscopic imaging of genetically encoded voltage and calcium influx sensors, can only record from 100s to 1000s of neurons simultaneously. Practical technologies that enable simultaneous mapping of neuronal activities from large brain volumes at cellular resolution currently do not exist. Here we propose to develop transparent polymer skulls with embedded miniature optical instruments that allows mapping of single-cell neuronal activities of up to a 45 mm2 area in cortex of a freely moving mouse at high temporal resolution. The imaging devices will be complemented with next generation spatially confined genetically encoded calcium and voltage indicators. This technology platform will leverage recent advances we have made in our laboratory ? 3D printed skull replacement implants that allow optical access to the whole dorsal cortex of the mouse, with miniaturized CMOS imaging sensors and microscopic optics incorporated onto the implant surface. The successful development of this technology will lead to fundamentally new experimental paradigms in neuroscience and enable new insights into the neuronal computations that underlie sensory perception, action and cognitive processes. Long term, this technology will lead to new classes of brain machine interfaces, enabling information reading and writing at unprecedented spatial and temporal scales.